title: Effects of tolcapone on working memory and brain activity in abstinent smokers: a proof-of-concept study.
abstract: BACKGROUND
  Dopamine levels in the prefrontal cortex (PFC) are thought to play an important role in cognitive function and nicotine dependence. The catechol-O-methyltransferase (COMT) inhibitor tolcapone, an FDA-approved treatment for Parkinson's disease, increases prefrontal dopamine levels, with cognitive benefits that may vary by COMT genotype. We tested whether tolcapone alters working memory-related brain activity and performance in abstinent smokers.
  
  
  METHODS
  In this double-blind crossover study, 20 smokers completed 8 days of treatment with tolcapone and placebo. In both medication periods, smokers completed blood oxygen level-dependent (BOLD) fMRI scans while performing a working memory N-back task after 24h of abstinence. Smokers were genotyped prospectively for the COMT val(158)met polymorphism for exploratory analysis.
  
  
  RESULTS
  Compared to placebo, tolcapone modestly improved accuracy (p=0.017) and enhanced suppression of activation in the ventromedial prefrontal cortex (vmPFC) (p=0.002). There were no effects of medication in other a priori regions of interest (dorsolateral PFC, dorsal cingulate/medial prefrontal cortex, or posterior cingulate cortex). Exploratory analyses suggested that tolcapone led to a decrease in BOLD signal in several regions among smokers with val/val genotypes, but increased or remained unchanged among met allele carriers. Tolcapone did not attenuate craving, mood, or withdrawal symptoms compared to placebo.
  
  
  CONCLUSIONS
  Data from this proof-of-concept study do not provide strong support for further evaluation of COMT inhibitors as smoking cessation aids.
authors.affiliation: Center for Interdisciplinary Research on Nicotine Addiction, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: rlashare@mail.med.upenn.edu.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Ashare
authors.forename: E Paul
authors.initials: EP
authors.lastname: Wileyto
authors.forename: Kosha
authors.initials: K
authors.lastname: Ruparel
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Goelz
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Hopson
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Valdez
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.forename: James
authors.initials: J
authors.lastname: Loughead
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
mesh_terms: D000293:Adolescent; D000328:Adult; D000339:Affect / Q000187:drug effects; D000368:Aged; D016739:Behavior, Addictive / Q000188:drug therapy / Q000503:physiopathology; D001577:Benzophenones / Q000494:pharmacology* / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D001931:Brain Mapping; D002394:Catechol O-Methyltransferase / Q000235:genetics; D065098:Catechol O-Methyltransferase Inhibitors; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D008875:Middle Aged; D009596:Nitrophenols / Q000494:pharmacology* / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000188:drug therapy* / Q000523:psychology*; D016540:Smoking Cessation; D000074606:Smoking Prevention; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy; D061485:Tobacco Use Cessation Devices; D000077867:Tolcapone; D055815:Young Adult
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D000077867:Tolcapone; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase
keywords: COMT; Nicotine; Smoking; Tolcapone; Working memory; fMRI